6. PROJECT SUMMARY/ABSTRACT: Craniofacial diseases are some of the most common of human birth defects and can be extremely variable in their severity and extent. There are both genetic and environmental causes of craniofacial disease and it is likely that a large portion of disease variability is due to complex interactions between multiple genes and the environment. It is our long-term objective to understand the mechanism of gene-environment interactions and how these interactions regulate disease severity. We have chosen to use Fetal Alcohol Spectrum Disorder (FASD) as a model of gene-environment interactions because FASD has variable craniofacial defects, has a known environmental cause (maternal alcohol consumption) and is clearly genetically regulated. However, we are lacking in even a basic understanding of the genetic loci that control susceptibility to ethanol-induced craniofacial disease. We have pioneered genetic screens to discover ethanol-interacting loci. Results from these screens demonstrate that members of the Bmp pathway interact synergistically with ethanol. The spectrum of these ethanol-induced phenotypes closely mirrors those present in gata3 mutants. Our preliminary results strongly suggest that the Bmp pathway acts in a network with Gata3 to control cell behaviors coordinated by the Wnt/PCP pathway In aim 1, we characterize the gene-ethanol and gene-gene interactions amongst these network members. In aim 2, we use unbiased transcriptomic approaches to identify critical gene clusters mediated by Bmp and Gata3. In aim 3, we explain how altered cell behaviors cause the craniofacial defects in our mutant lines. Because of the conservation of gene function between zebrafish and humans, the results from our studies will provide key insights into the genetic loci that interact with themselves and the environment to modulate human craniofacial disease severity.